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Bernard Soulier syndrome

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NORD is very grateful to Irene Roberts, MD, Professor of Paediatric Haematology at Imperial College, London, for assistance in the preparation of this report.

Synonyms of Bernard Soulier syndrome

Disorder Subdivisions

General Discussion

Bernard-Soulier syndrome (BSS) is a rare inherited disorder of blood clotting (coagulation) characterized by unusually large platelets, low platelet count (thrombocytopenia) and prolonged bleeding time (difficulty in clotting). Affected individuals tend to bleed excessively and bruise easily. Most cases of Bernard-Soulier syndrome are inherited as an autosomal recessive genetic trait.

Symptoms

The symptoms of Bernard-Soulier Syndrome, which are typically apparent at birth and continue throughout life, may include the tendency to bleed excessively from cuts and other injuries, nosebleeds (epistaxis), and/or an unusually heavy menstrual flow in women. People with this disease also bruise easily and the bruises tend to linger. Bleeding from very small blood vessels under the skin (subcutaneous) may cause small or widespread areas of small red or purple colored spots (purpura or petechiae).

Causes

BSS is a genetic disorder that affects the ability of the platelets in the circulating blood to bind with a damaged blood vessel and hence to clot blood. These platelets are missing an essential protein called glycoprotein Ib-IX-V (GPIb) that normally sticks out of the platelet's surface and binds with another protein found in the circulating blood called von Willebrand factor. If one of these proteins is missing or abnormal, they cannot bind correctly to begin the clotting process and excessive bleeding results.

BSS is caused by a mutation in any one of four genes for the GPIb protein. The abnormal genes have been mapped to chromosomes 17p12, 22q11.2, 3q21 and 3q29.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated as "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 17p12" refers to band 12 on the short arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Bernard-Soulier Syndrome is usually inherited as an autosomal recessive genetic trait.
Recessive genetic disorders occur when an individual inherits an abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance that a child receives normal genes from both parents and is genetically normal for that particular trait is 25%. The risk is the same for males and females.

Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Affected Populations

Bernard-Soulier Syndrome is a rare bleeding disorder that affects males and females in equal numbers. More than 100 cases have been reported worldwide.

Related Disorders

Symptoms of the following disorders can be similar to those of Bernard- Soulier Syndrome. Comparisons may be useful for a differential diagnosis:

May-Hegglin Anomaly is a rare inherited disorder of blood platelets and certain white blood cells characterized by abnormally large platelets. Some people with this disorder have symptoms from birth while others are without symptoms for life. Symptoms may include nosebleeds, purple colored spots on the skin (purpura), excessive bleeding from the mouth during dental work, and/or headaches. Some people with May-Hegglin Anomaly may experience muscular weakness on one side of the body because of abnormal bleeding inside the brain (intracranial hemorrhage). (For more information on this disorder, choose "May-Hegglin" as your search term in the Rare Disease Database.) May Hegglin does not usually cause bleeding in newborn babies unlike BSS.

Hemophilia is a rare inherited blood clotting (coagulation) disorder caused by inactive or deficient blood proteins (usually factor VIII). Factor VIII is one of several proteins that facilitates blood clotting. Hemophilia is found in males almost exclusively and can be classified as mild, moderate, or severe depending upon the percentage of clotting factor present in a person's blood. The most serious symptom of hemophilia is uncontrolled internal bleeding that may begin spontaneously without any apparent cause. Internal bleeding may cause permanent damage to the joints and muscles. People with hemophilia bleed for a longer period of time than people who have the normal percentage of active clotting factors in their blood. Bruises and trauma can trigger episodes of serious internal bleeding in males with this disorder. (For more information on this disorder, choose "Hemophilia" as your search term in the Rare Disease Database.)

Thrombasthenia of Glanzmann and Naegeli is a rare inherited blood clotting (coagulation) disorder characterized by impaired function of the specialized red blood cells (platelets) that are essential for proper blood clotting. Symptoms may include abnormal bleeding, and/or hemorrhage, easy bruising, bleeding from the gums, nosebleeds (epitaxis), and/or large red or purple colored spots on the skin (purpura). The symptoms of Thrombasthenia of Glanzmann and Naegeli are not progressive and may improve with age. (For more information on this disorder, choose "Thrombasthenia" as your search term in the Rare Disease Database.)

Von Willebrand Disease is a rare inherited blood clotting (coagulation) disorder that varies widely in its effects. Most people have relatively mild diseaseand are not diagnosed until they are adults. A small number start to have problems during infancy or early childhood, such as prolonged bleeding and an abnormally slow blood clotting time. Symptoms may include bleeding from the gastrointestinal tract, nosebleeds, bleeding from the gums, and/or easy bruising. People with this disorder may also bleed easily after injury, childbirth, and/or surgery. These symptoms occur because of a deficiency of factor VIII and the von Willebrand factor. (For more information on this disorder, choose "von Willebrand" as your search term in the Rare Disease Database.)

Storage Pool Disease (SPD) is a rare inherited disorder of blood platelets characterized by clotting dysfunction due to the platelets' inability to store certain clotting factors. Symptoms occur mostly in women and may include mild bleeding, nosebleeds, and/or slightly heavier than normal menstrual periods. People with Storage Pool Disease may also have abnormally low levels of blood platelets (thrombocytopenia).

Platelet disorders are also associated with congenital conditions such as Wiskott-Aldrich Syndrome, Down Syndrome, and Thrombocytopenia with Absent Radius Syndrome. For more information on these disorders choose "Wiskott- Aldrich," "Down Syndrome," and "Thrombocytopenia with Absent Radius," as your search terms in the Rare Disease Database.)

Standard Therapies

Diagnosis
The diagnosis of Bernard-Soulier syndrome is made by a combination of blood testing to reveal whether platelets are at abnormally low levels (thrombocytopenia), microscopic examination to determine the presence of abnormally large platelets and irregularly shaped platelets, and biochemical tests to determine the capacity of the platelets to initiate clotting. Molecular genetic testing is available.

Treatment
Platelet transfusion is used to treat Bernard-Soulier syndrome when surgery is necessary or when there is a risk for life-threatening hemorrhage. People with this disorder should not take aspirin or other related drugs because these medications affect the blood's ability to clot (platelet aggregation). It is suggested that acetaminophen, which is present in medications such as Tylenol, is used for the relief of mild pain.

Genetic counseling may be of benefit for people with Bernard-Soulier syndrome and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Desmopressin acetate (DDAVP) has been shown to shorten bleeding time in some, but not all, patients with BSS. It may be useful for minor bleeding episodes.

More recently, recombinant activated factor VII has been used in patients with congenital platelet disorders including BSS.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Bernard Soulier syndrome Resources

Organizations:

References

TEXTBOOKS
Rao AK. Bernard-Soulier Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:378.

Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:927.

Hoffman R, Benz Jr EJ, Shattil SJ et al. Eds. Hematology: Basic Principles and Practice. 2nd ed. Churchill-Livingstone, Inc. New York, NY; 1995:1524, 1910.

Bennett JC, Plum F. Eds. Cecil Textbook of Medicine. 20th ed. W.B. Saunders Co., Philadelphia, PA; 1996:985

JOURNAL ARTICLES
Nurden A, Nurden P. Advances in our understanding of the molecular basis of disorders of platelet function. J Thromb Haemost 2010; (Suppl1) 9: 76-91.

Alamelu J, Liesner R. Modern management of severe platelet function disorders. Br J Haematol 2010;149: 813-823.

Peitsidis P, Datta T, Pafilis I et a.l Bernard Soulier syndrome in pregnancy: a systematic review. Haemophilia 2010;16: 584-591

Nurden, A.T., and Nurden, P. Inherited thrombocytopenias. Haematologica 2007;92, 1158-1164.

Nurden AT, Combrie R, Claeyssens S, et al. Heterozygotes in the bernard-soulier syndrome do not necessarily have giant platelets or thrombocytopenia. Br J Haematol. 2003;120:716-17.

Kunishima S, Kamiya T, Saito H. Genetic abnormalities of Bernard-Soulier syndrome. Int J Hematol. 2002;76:319-27.

Nakagawa M, Okuno M, Okamoto N, et al. Bernard-Soulier syndrome associated with 22q11.2 microdeletion. Am J Med genet. 2001;99:286-88.

Toren A, Rozenfeld-Granot G, Rocca B, et al. Autosomal-dominant giant platelet syndromes: a hint of the same genetic effect as in Fechtner syndrome owing to a similar genetic linkage ro chromosome 22q11-13. Blood. 2000;96:3447-51.

Poon MC, d'Oiron R. Recombinant activated factor VII (NovoSeven) treatment of platelet-related bleeding disorders. International Registry on Recombinant Factor VIIa and Congenital Platelet Disorders Group. Blood Cloagul Fibrinolysis. 2000;11 (Suppl 1):S55-68.

Hayashi T, Suzuki K. Molecular pathogenesis of Bernard-Soulier syndrome. Semin Thrommb Hemost. 2000;26:53-59.

Noda M, Fujimura K, Takafuta T, et al. Heterogeneous expression of glycoprotein Ib, IX and V in platelets from two patients with Bernard-Soulier syndrome caused by different genetic abnormalities. Thromb Haemost. 1995;74:1411-15

INTERNET
McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Entry Number; 231200 http://omim.org/entry/231200 Last Edit Date:9/14/11 Accessed on:January 26, 2012.

Geil JD. Bernard-Soulier Syndrome. eMedicine. Last Updated: June 30, 2009
www.emedicine.com/ped/topic230.htm Accessed On: January 26, 2012.

Report last updated: 2012/02/01 00:00:00 GMT+0